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Among chemotherapeutics, temozolomide is considered as the first\u2010line drug for GBM therapy, but the treatment outcome is not satisfactory. Notably, regorafenib, an oral multi\u2010kinase inhibitor, has been reported to exert a markedly superior effect on GBM suppression compared with temozolomide. However, poor site\u2010specific delivery and bioavailability significantly restrict the efficient permeability of regorafenib to brain lesions and compromise its treatment efficacy. Therefore, human H\u2010ferritin (HFn), regorafenib, and Cu\n                    <jats:sup>2+<\/jats:sup>\n                    are rationally designed as a brain\u2010targeted nanoplatform (HFn\u2010Cu\u2010REGO NPs), fulfilling the task of site\u2010specific delivery and manipulating autophagy and cuproptosis against GBM. Herein, HFn affords a preferential accumulation capacity to GBM due to transferrin receptor 1 (TfR1)\u2010mediated active targeting and pH\u2010responsive delivery behavior. Moreover, regorafenib can inhibit autophagosome\u2010lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Furthermore, Cu\n                    <jats:sup>2+<\/jats:sup>\n                    not only facilitates the encapsulation of regorafenib to HFn through coordination interaction but also disturbs copper homeostasis for triggering cuproptosis, resulting in a synergistical effect with regorafenib\u2010mediated lethal autophagy arrest against GBM. Therefore, this work may broaden the clinical application scope of Cu\n                    <jats:sup>2+<\/jats:sup>\n                    and regorafenib in GBM treatment via modulating autophagy and cuproptosis.\n                  <\/jats:p>","DOI":"10.1002\/smll.202205354","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T14:46:42Z","timestamp":1668782802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Brain\u2010Targeted HFn\u2010Cu\u2010REGO Nanoplatform for Site\u2010Specific Delivery and Manipulation of Autophagy and Cuproptosis in Glioblastoma"],"prefix":"10.1002","volume":"19","author":[{"given":"Wenhui","family":"Jia","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center West China Hospital and West China School of Basic Medical Sciences &amp; Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy  Chengdu 610041 P. 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